This R21 application requests funding for a two-year exploratory/developmental study to better characterize children and adolescents with severe mood dysregulation (SMD), and to conduct a pilot study of combination pharmacotherapy as a basis for designing future intervention trials. SMD is characterized by severe, non-episodic irritability, hyperarousal, and aggression. Evidence suggests that recent increases in the diagnosis of pediatric bipolar disorder might be due to misidentification of youth with SMD, who are nonetheless at increased risk for social and academic failure, cognitive problems, physical abuse, and adult depression. Currently, many of these children are treated with antipsychotic medications that, although sedating, are non-specific and associated with significant health risks, including excessive weight gain and other metabolic difficulties. Given the increased rates of lifetime attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety among SMD-affected individuals, it is possible that medicines that are more specific to these disorders, such as stimulants and antidepressants, as well as psychosocial treatments, might prove more acceptable to patients and families. This project will inform ongoing discussions on the proper diagnostic approach to SMD and provide a foundation for the design of definitive intervention studies. The proposed project will carefully assess children and adolescents with SMD, including evaluations for co-occurring psychiatric and learning disorders, neuropsychological testing, and, brain imaging with electroencephalography (EEG). This information will be compared with a large existing database of youth with established psychiatric conditions, as well as non-clinical control subjects. Participants will proceed to a two- stage medication trial. First, all participants will have a 4-week open-label stimulant trial with dextro- methylphenidate extended release (d-MPH-XR) to determine an optimal dose. Once the dose is established, participants will be randomized to an additional 8 weeks with double-blind fluoxetine, a selective serotonin reuptake inhibitor used for treatment of depression and anxiety, versus placebo taken in combination with the stimulant. Participants will be closely monitored for clinical response and potential side effects. Statistical analyses will assess potential differences between SMD and other disorders, and provide preliminary information on the potential benefits of these medications in SMD treatment. There will be particular emphasis on assessing the usefulness of various outcome measurements in anticipation of future research. The application is consistent with NIMH priorities, including the development of new ways to classify mental disorders, identification of biomarkers that differentiate disorders, treatment of individuals with comorbid conditions, and exploring use of an infrequently researched area, namely combination pharmacotherapy in children and adolescents. PUBLIC HEALTH RELEVANCE: This study addresses the mission of the NIMH by further characterizing a previously under-recognized group of children and adolescents that are at high risk for lifelong psychopathology and functional impairment. Information derived, in conjunction with use of a large pre-existing database, may lead to more biologically informed approaches to early identification, diagnosis, and personalized treatment of SMD-affected individuals, with a potential to preempt subsequent adult mental illness. This project will establish a basis for ongoing research efforts in SMD.